Degenerative disc disease and associated spinal instability are the major cause of chronic low back pain in western civilization. Surgical options, including artificial discs, have been disappointing and only a very small percentage of back pain sufferers (~1 in 20) elect to have surgery. The specific aims of this program focus on the design of a nonsurgical tissue engineering solution that would become the first line of therapy for degenerative disc disease. Orthopeutics' key innovation is the use of nontoxic injectable agents that increase collagen crosslinking in the extracellular matrix of the disc annulus fibrosus, mimicking the body's own efforts to stabilize aged and mechanically unstable discs. Preliminary in vitro studies which form the basis of this Phase I proposal show a 2 to 3-fold improvement in durability, a 4-fold improvement in joint stability, and doubled nutritional supply/waste removal to center of the disc. In vivo proof of concept studies have demonstrated a mild treatment effect, with no significant histological changes in the annulus fibrosus. This Phase I study will characterize several candidate reagents with regard to crosslinking effect and diffusive transport using an ex vivo bovine/porcine disc model. Crosslinking effect will be assessed through mechanical testing, thermal analysis, and protease digestion. Diffusive transport will be assessed through time lapse visualization studies using dyes of representative molecular weights, as well as mapping of treated discs using thermal analysis. A Phase II study of the most promising formulation would focus on optimizing reagent activity, durability of effect, and safety; and developing a product suitable for human clinical trials. [unreadable] Back pain and disability associated with spinal degeneration and instability is one of the costliest and most prevalent health problems. Between 4.7 percent (medical records) and 9.4 percent (population surveys) of the US population seeks professional health care annually (1990) for low back pain, a prospective patient population in excess of 15 million/year. In the face of this great unmet clinical need, the development of regenerative medicine techniques to reverse the process of spinal disc degeneration has been recognized as an important research opportunity by NIAMS. [unreadable] [unreadable] [unreadable] [unreadable]